An important clinical trial candidate, (6R,7S) 7-(R)-phenylglycylamido-3-chloro-1-azabicyclo[4.2.0]-oct-2-ene-8-one-2-car boxylic acid (loracarbef), claimed in U.S. Pat. No. 4,708,956, may be synthesized by various routes. One of the more noteworthy total syntheses of loracarbef is that made possible by Evans and Sjogren, U.S. Pat. No. 4,665,171. The Evans and Sjogren methodology provides a chiral 2+2 (ketene plus imine) cycloaddition, and accordingly, entry to a wide variety of chiral cis .beta.-lactams. However, the Evans and Sjogren methodology requires the utilization of a chiral auxiliary of the formula ##STR1## in the 2+2 cycloaddition with a Schiff's base, wherein X' is chloro, bromo, trifluoroacetoxy, or OP(=)X.sub.2, wherein X is halogen. The above chiral auxiliary can be synthesized in seven steps from L-phenylglycine. The resulting cycloaddition provides compounds of the formula ##STR2## wherein Ar is phenyl, C.sub.1 -C.sub.4 alkylphenyl, halophenyl, C.sub.1 -C.sub.4 alkoxyphenyl, naphthyl, thienyl, furyl, benzoenyl, or benzofuryl; R is phenyl, C.sub.1 -C.sub.4 alkylphenyl, C.sub.1 -C.sub.4 alkoxyphenyl, or halophenyl; Y is --CH.dbd.CH--, or --CH.sub.2 -CH.sub.2 -; and R' is phenyl, C.sub.1 -C.sub.4 alkylphenyl, C.sub.1 -C.sub.4 alkoxyphenyl, halophenyl, furyl or naphthyl.
The obvious shortcomings of the Evans and Sjogren route are that a very expensive starting material, L-phenylglycine(when Ar is phenyl), is used, the chiral auxiliary is synthesized in several steps in linear fashion; and further, the chiral auxiliary is removed and discarded using Li/NH.sub.3 /t-C.sub.4 H.sub.9 OH to provide a free 3-amino-azetidinone.
As an achiral alternative, Hatanaka et al., Tetrahedron Letters, Vol. 24, No. 49, pp. 4837-4838 (1983), provides a method for preparing a 3-hydroxy(.+-.)1-carbacephalosporin via a 2+2 cycloaddition much in the same fashion as that of Evans and Sjogren, but with azidoacetyl chloride rather than a chiral auxiliary as the ketene source. The Hatanaka methodology provides many of the same intermediates as does the Evans and Sjogren synthesis, albeit in achiral form. The advantage of the achiral synthesis of Hatanaka is economy of steps and starting material. However, an achiral strategy necessitates a resolution of the cis-racemic .beta.-lactam at some point during the synthesis because a chiral (.beta..beta.)system is ultimately desired.